Tumor cells and T lymphocytes cary forward initially similar and subsequently distinct bioenergetic regulation through AMPK. Dr Guerra Authentic Biochemistry 30 Dec. 2020

 Early stage TCR activated T cells with rampant lactic acid fermentation, fail to  maintain adequate ATP levels , especially when glucose is limiting.This decrease in ATP relative to ADP+AMP results in the activation of AMPK, which inhibits mTOR activity all all sunsequent anabolism especially assocaited for  T cell proliferation. Indeed, induced Loss of AMPKα1, will sythetically restore  mTOR signaling and T cell cytokine production, but not proliferation. Although loss of AMPK can restore some functions in glucose-restricted T cells, the cells do not initiate metabolic adaptations necessary to recover ATP levels. In vivo, AMPKα1-deficient T cells have decreased mitochondrial respiration, flux of glutamine into the mitochondria, and ATP:AMP ratios, and therefore fail to proliferate and function effectively.

In cardiac and skeletal muscle, AMPK phosphorylates the bifunctional enzyme at a unique SER residue which induces the PFK-2 activation over the phosphatase activity thus stimulating glycolysis and overcoming hypoxia. Hypoxia renders the mitochondrial electron-transport chain-oxidative phosphorylation pathway non-functional as molecular oxygen is the ultimate electron acceptor becoming reduced to water. With depleted oxygen as in stress and in heavy skeletal muscle contraction, glycolysis must be stimulated as AMP levels rise. AMP also controls PFK-1 directly

In tumors, the rate of translation of HIF-1a mRNA in cancer cells is dependent upon the activity of the mammalian target of rapamycin (mTOR), which in turn is determined by the activity of upstream tumor suppressor proteins and oncoproteins. HIF-1α plays a key role in stimulating glycolic enzymes and in blocking mitochondrial activity. LncRNAs can also regulate Akt and AMPK pathways. Akt may increase oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation.

Relevant Research References

Cell Research volume 30, pages649–659(2020)

 Molecular Cancer July 2017. 16(1)DOI: 10.1186/s12943-017-0699-3

Genomics, Proteomics & Bioinformatics Volume 14, Issue 1, February 2016, Pages 42-54

J BiolChem. 2011 Apr 8; 286(14): 11937–11950.

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